Steroidal hormone intermediates and preparation of the same



Patented July 4, 1944 STEROIDAL HORMONE INTERMEDIATES AND PREPARATION OFTHE SAME Russell Earl Marker, State College, Pa., asslgnor to Parke,Davis & Company, Detroit, Mich, a corporation oi. Michigan i No Drawing.Application February 5, 1940, Serial No. 317,419

6 Claims. (CL 260-397.!)

This invention relates to steroidal hormone intermediates andpreparation of the same, and, more particularly, to the preparation ofnew steroidal sapogenin derivatives useful as intermediates for themanufacture of hormones.

saturation of the ring system and the number of substituents attached tothese rings.

The structures 01' rings A and B of these compounds are shown below:

One of the objects of this invention is to prepare new steroidalsapogenin derivatives which A can readily be converted to pregnanederivatives.

In my copending application, Serial No. 393,- A B 667, filed May 15,1941, I have set forth the prep- 10 no aration of new sapogeninderivatives which I designate as pseudo-sapogenins and have also set Hforth the manner in which the pseudo-sapogenins cmomenin may be oxidizedto form a -ilfl-keto-pregnene compounds, 1. e. steroids having in ring Dthe structure A B cm 0 Ho Dioegenin cm In my copending applicationSerial No.'393,668, A filed May 15, .1941, I have disclosed and claimeda no certain group of A -20-keto-pregnene compounds A B which are easilyprepared from the readily avail- H0 able sarsapogenin. The presentapplication describes another valuable group of A -20-keto-pregnenecompounds having at C2, C3 and Co a member of the class of groupings =0,11 H I where X is one of the class 0H, Oacy1,

--O a1kyl, -Oaryl, Oara1kyl and halogen or similar group hydrolyzable toOH. not more In this new class of compounds the ester, ether and halogenderivatives are usually made from the corresponding free hydroxyliccompounds by any of the known methods for converting a secondary alcoholinto its ester, ether or halogen derivative. For example, esters aremade by reacting the hydroxyl compounds with carboxylic acid acylatingagents such as acid chlorides, acid anhydrides and the like. Halides canbe made,

than one of the g p n at C: and Ca being 40 for example, by reacting thehydroxyl compound H with a halogenating agent such as thionyl ch10-ride, phosphorus halide, and the like. The halo H gen derivatives can,ifdesired, be converted, by

when the c3 substituent'gmup is a oxygenated reaction with alkali metalalcoholates or alkali group for examp 18 The ethers may also be made bycondensing the OH O-acyl or other alcohols in presence of agentsfacilitat- H H ing elimination of water from the reactants, such and thelike. a vas sulfuric or phosphoric acids.

h compounds of this invention m y be 0 The invention is illustrated bythe following tained, for example, from the known sapogenins, examples.chlorogenin, diosgenin and gitogenin which difier from one another onlyin regard to the connections between rings A and B, the degree 01'Example 1 (a) A mixture of 2.5 grams of chlorogenin and 45 metalphenolates, into the corresponding ethers.

alcoholic sapogenin derivatives with themselves hours.

30 cc. of acetic anhydride is heated at 200 for The acetic anhydride isthen evaporated in vacuo and the syrupy residue hydrolyzed with hotalcoholic potassium hydroxide. The small white crystals which separateon dilution are collected and washed well with alcohol. The product thusobtained is pseudo-chlorogenin and after recrystallization from acetonehas the M. P. 268-270", C. It gives a large depression with a sample ofchlorogenin. The substance is very sparingly soluble in acetone, ethylacetate, ether, alcohol and similar solvents.

(b) 2 grams of psuedo-chlorogenin as thus prepared are dissolved in 300cc. of acetic acid and a solution of 2 grams of chromic anhydride in 20cc. of 80% acetic acid is added at room temperature. After standing forabout an hour, a small amount of alcohol is added and most of 1 hour onthe steam bath. The mixture is diluted with water and extracted withether and the ethereal extract washed well with water and dilute alkali.The ether is removed on the steam bath and the residue crystallized fromslightly diluted methanol.

- nanetrione-3,6,20.

the acetic acid removed by vacuum distillation.

The residue is dissolved in ether and washed well with water and dilutesodium hydroxide solution. The ethereal extract is evaporated to drynesson a steam bath and the residue recrystallized from alcohol. Thus thereis obtained crystals of allo-pregnenetrione-3,6,20, M. P. 226 C.

(c) Five-tenths of a gram of A -pregnenetrione-3,6,20 is dissolved in100 cc. of acetic acid and shaken in the presence of 0.5 gram of Adamsplatinum: oxide catalyst in a hydrogen atmosphere at about 40 lbs.pressure for 3 hours. Then the catalyst is removed by filtration and theacetic acid evaporated in vacuo. The residue may be crystallized fromacetone to give allopregnanetriol-3,6,20 as white crystals. On oxidationwith an equal weight of chromic anhydride in acetic acid solution atroom temperature and working up the product, there is obtainedallo-pregnanetrione-3,6,20 of M. P. 235 C.

Example 2 (a) 'A mixture of 2 grams of diosgenin, 30 cc. of benzoylchloride and 15 grams of freshly fused sodium acetate is heated in anoil bath at 220 C. for 10 hours. Then the mixture is distilled in vacuountil no more distillate can be collected at 200 C. and 10 mm. pressure.Theresidue in the distilling flask is cooled and alcoholic sodiumhydroxide solution is added. After warming for one-half hour, themixture is diluted with water and ether, and the layers separated. Theethereal layer is washed with water and dilute sodium hydroxide and thenevaporated to dryness on a steam bath. This residue is pseudo-diosgenin.It may be purified by crystallization from slightly diluted alcohol andis thus obtained as white c ystals which readily decolorize bromine inacetic, acid.

(1)) One gram of pseudo-diosgenin is dissolved in 100 cc. of aceticacid. Five cc. of sulfuric acid low residue may be recrystallizedfromacetone.

to give yellow crystals of A -pregnadiene-trione-3.6.

(c) To 200 mgs. of the above A -pregnadienetrione-3,6,20 in 10 cc. ofacetic acid is added 500 mgs. of zinc dust and the mixture heated forExample 3 (a) One gram of gitogenin is heated in a bomb tube with 20 cc.of acetic anhydride for 10 hours. The acetic anhydrideis removed invacuo and the residue warmed for one-half hour with an excess ofalcoholic potassium hydroxide solution. Then the mixture is dilutedwith'water and extracted with ether. The ethereal extract is washed withwater and the ether evaporated on the steam bath. The residue ispseudo-gitogenin which may be purified by crystallization from methanolto give white crystals.

(b) Seven-tenths of a gram of-pseudo-gitoenin are warmed'on a steam bathwith 5 cc. of nitric acid for one-half hour. The mixture is cooled,diluted with water and ether extracted. The ethereal extract is shakenwith sodium hydroxide solution and the sodium hydroxide solution thenacidified with dilute hydrochloric acid. The precipitate is collected,washed well with water and recrystallized from chloroform. The

- acid thus obtained is an etio-bilianic acid derivative in which ring Ahas been opened. Itmay be represented by the following formula,

CH: CH!

COOH

Example 4 (a) Pseudo-chlorogenin is prepared as described, for instance,in Example 1.

(b) A solution of 2 g. of pseudo-chloregenin in 300 cc. of acetic acidis mixed with 0.5 g. of

Hooc

platinum oxide catalyst, and the suspensionshaken in a hydrogenatmosphere at room temperature and 40 lbs. pressure for three hours.Then the mixture is filtered, and the filtrate evaporated. to dryness.The residue is crystallized from alcohol and this givesdihydro-pseudochlorogenin, M. P. 270. This substance gives a depressionin melting point with pseudo-chlorogenin which also has M. P. 270.

(c) A mixture of 1 g. of dihydro-pseudochlorogenin and 10 cc. of aceticanhydride is refluxed for a half hour. Then the excess acetic anhydrideis removed in vacuo and the residue crystallized from methanol to givepure dihydropseudo-chlorogenin triacetate, M. P. 150.

(d) To a solution of 4 grams of dihydropseudo-chlorogenin diacetate in200 cc. of acetic acid is added a solution of 6 grams of chromicanhydride in 50 cc. of 80% acetic acid. After standing at room.-temperature for minutes, water is added and the mixture extracted withether. -The ethereal layer is washed with water This product isallo-prefl and 3% sodium hydroxide solution. The ethereal extract isevaporated and this gives ri -allopregnenone-20-dlol-3,6. v r

- (e) A mixture of 250 mgms. of A allo-pregnenone-20-diol-3,6, 120 cc.of absolute alcohol and 1 gram of palladium-barium sulfate catalyst isshaken withhydrogenat 1 atmosphere pressure at room temperature for 90minutes. The catalyst is removed by filtration and the solventevaporated in vacuo. The residue is crystallized l0 1 from aqueousalcohol toqgive allo-pregnanone- 20-dio1-3,6, M. P. 210; v

The palladium-barium sulfate catalyst used in this preparation isprepared according to the directions given in Houben-WeylArbeitsmethoden d. Organischen Chemie, 3rd ed; II, 323;

What I claim as my invention is:

1. A A -unsaturated-20-keto-pregnene substituted in rings A and B at C-3and one of 0-2 and 0-6 by two hydroxyl groups. J 2. A compound havingthe formula,

I OH:

on, on"

3. A A"-unsaturated-20-keto-pregnene substituted in rings A and Bat C:and one of C: and C by a member of the class consisting of 0H and groupshydrolyzable to OH.

4. A compound having the formula,

I v t CH:

1 HI CH 1 =0 6. A"-a'.llo-pregnenone-20-diol-3,8. RUSSELL EARL MARKER;

